Thiophene compounds substituted at the 2-position, especially 2-acyl-substituted thiophenes such as 2-acetylthiophene, 2-thiophenecarboxylic acid and 2-thiophenecarbonyl chloride, are used as intermediates in the synthesis of pharmaceuticals. For example, 5-chloro-2,3-dihydro-2-oxo-3-(2-thienylcarbonyl)-1H-indole-1-carboxamide ("tenidap") involves, as one of its synthetic steps, the reaction of a 2-carbonyl-substituted thiophene such as 2-thiophenecarbonyl chloride with an appropriate indole compound. 2-Thiophenecarbonyl chloride is most simply prepared from 2-acetylthiophene first by the halo form reaction to produce 2-thiophenecarboxylic acid followed by transformation to the acid chloride using thionyl chloride or an equivalent reagent, thus: ##STR1##
2-Acetylthiophene is normally prepared by Friedel-Crafts acetylation of thiophene with acetic acid or an activated form thereof such as acetic anhydride. The product is normally purified by distillation and it regularly contains from 1-2% of the 3- acetylthiophene as an impurity. This by-product cannot easily be removed, because the substances boil within a few degrees of each other. For most purposes, 2-acetylthiophene of 98-99% purity is adequate.
However, when 2-thiophenecarbonyl chloride is used in the synthesis of the drug tenidap, it has been found that even a low level of 3-thiophenecarbonyl chloride contaminating the 2-thiophenecarbonyl chloride in this synthesis leads to an unacceptable quality of the final product, requiring further purification. The final product is purified only with difficulty, and with attendant losses of expensive product.
The 2-thiophenecarboxylic acid and the 2-thiophenecarbonyl chloride produced from 2-acetylthiophene by the above reaction are still contaminated with the corresponding 3-substituted products. These impurities are so similar to the desired 2-substituted products that they cannot effectively be removed therefrom without suffering substantial losses of the desired product.
It is an object of the present invention to provide a novel process for preparing 2-substituted thiophenes essentially free from the corresponding 3-substituted thiophene impurities.